Role of UCP2 in Diabetic Stroke Brain

UCP2 在糖尿病中风脑中的作用

基本信息

批准号：
7633406
负责人：
P. Andy Li
金额：
$ 23.1万
依托单位：
NORTH CAROLINA CENTRAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7633406
关键词：
Ablation Achievement Acidosis Address Adipose tissue Adverse effects Area Brain Brain Injuries Calcium Cardiac Cause of Death Cell Death Cell Survival Cells Cerebral Ischemia Cerebrum Cessation of life Characteristics Clinical Clinical Data Complications of Diabetes Mellitus Conflict (Psychology)Development Diabetes Mellitus Diabetic mouse Disease Down-Regulation Electron Transport Endothelial Cells Energy Metabolism FADH2 Genes Genetic Glucose Glutathione Goals Hyperglycemia Hypoxia In Vitro Incidence Infarction Inflammatory Response Injection of therapeutic agent Injury Inner mitochondrial membrane Ischemia Ischemic Brain Injury Ischemic Stroke Knock-out Lead Mediating Membrane Membrane Potentials Mitochondria Mitochondrial Membrane Protein Modeling Molecular Mus NADH Neurons Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Oxygen Pathogenesis Pathway interactions Patients Permeability Peroxonitrite Phase Physiological Production Proteins Protons Reactive Oxygen Species Reperfusion Therapy Reporting Research Personnel Respiration Risk Factors Role Signal Pathway Signal Transduction Simulate Skeletal Muscle Staging Streptozocin Stroke Superoxides Therapeutic Tissues Transgenic Mice Transgenic Organisms Transient Cerebral Ischemia Trauma United States Up-Regulation apoptosis inducing factor caspase-3 clinically relevant cytochrome c deprivation diabetic disability glucose metabolism in vivo mitochondrial membrane mitochondrial uncoupling protein novel therapeutic intervention overexpression prevent pro-caspase-9 programs protective effect protein expression

项目摘要

DESCRIPTION (provided by applicant): Diabetes mellitus (DM) is the sixth and stroke is the third leading cause of death in the United States. Although both experimental and clinical data have shown that diabetic hyperglycemia (HG) augments brain damage due to cerebral ischemia, the molecular mechanisms underlying this important, clinically relevant phenomenon are poorly defined. Preliminary studies suggest that HG enhances the superoxide production of mitochondrial origin and causes mitochondria! functional and morphological alterations in the early stage of reperfusion following a transient cerebral ischemia. HG-enhanced reactive oxygen species (ROS) formation may be caused by increased proton potential across the inner mitochondrial membrane due to excessive extrusion of protons donated from NADH and FADH2 through glucose metabolism. Mitochondrial uncoupling proteins (UCPs) dissipate the mitochondrial proton gradient by transporting H+ across the inner membrane, thereby stabilizing the mitochondrial membrane potential and reducing the formation of ROS. However, existing eveidence provids conflicting results to whether UCP2 is neuroprotective or neurodestructive. Our Central Hypothesis is that diabetic hyperglycemia enhances brain damage during stroke by overproducing ROS from the mitochondrial electron transport chain (ETC) due to increased extrusion of protons that perturbs AM^m. Accordingly, if the membrane potential is stabilized by upregulation of UCP2 the formation of ROS may be reduced and the diabetes-exacerbated stroke damage may be prevented. Using in vitro neuronal cultures that simulate in vivo diabetic and ischemic stroke conditions and an in vivo stroke model in Tg-UCP2, KO-UCP2 and genetic background matched C57BL/6J mice under both non- DM and DM conditions, the objectives of this study are to: 1) determine the pathways leading to ROS production after in vitro oxygen deprivation (OD) in cultured neurons mimicking in vivo diabetes and stroke conditions, 2) determine if deletion of the UCP2 gene augments and overexpression of UCP2 prevents HG- enhanced brain damage using both in vitro and in vivo ischemia models, and 3) determine the pathways by which UCP2 exerts its protective effects. Our successful achievement of this goal should significantly contribute to the current understanding of this clinical problem and may lead to the development of new therapeutic approaches, e.g. via manipulation of UCPs expression in the brain as a treatment for the disease

描述（由申请人提供）：在美国，糖尿病 (DM) 是第六大死因，中风是第三大死因。尽管实验和临床数据均表明糖尿病高血糖 (HG) 会加重脑缺血引起的脑损伤，但这一重要的临床相关现象背后的分子机制尚不清楚。初步研究表明HG增强线粒体来源的超氧化物产生并导致线粒体！短暂性脑缺血后再灌注早期的功能和形态变化。 HG 增强的活性氧 (ROS) 形成可能是由于葡萄糖代谢过程中 NADH 和 FADH2 提供的质子过度挤出，导致线粒体内膜质子电位增加所致。线粒体解偶联蛋白（UCP）通过跨内膜转运 H+ 来消除线粒体质子梯度，从而稳定线粒体膜电位并减少 ROS 的形成。然而，现有证据对于 UCP2 具有神经保护作用还是神经破坏作用提供了相互矛盾的结果。我们的中心假设是，糖尿病性高血糖会通过干扰 AM^m 的质子挤出增加，导致线粒体电子传递链 (ETC) 过量产生 ROS，从而加剧中风期间的脑损伤。因此，如果通过上调UCP2来稳定膜电位，则可以减少ROS的形成，并且可以预防糖尿病加剧的中风损伤。使用模拟体内糖尿病和缺血性中风条件的体外神经元培养物以及非糖尿病和糖尿病条件下 Tg-UCP2、KO-UCP2 和遗传背景匹配的 C57BL/6J 小鼠的体内中风模型，本研究的目的目的是：1) 确定模拟体内糖尿病和中风条件的培养神经元在体外缺氧 (OD) 后导致 ROS 产生的途径，2) 确定 UCP2 基因的删除是否会增强使用体外和体内缺血模型，UCP2 的过度表达可防止 HG 增强的脑损伤，3) 确定 UCP2 发挥其保护作用的途径。我们成功实现这一目标将极大地有助于当前对这一临床问题的理解，并可能导致新治疗方法的开发，例如：通过操纵大脑中 UCP 的表达来治疗该疾病